This Report involves work collected under protocol 04-M-0222 (NCT00088699). Our research suggests that the glutamatergic system is involved in the mechanism of action of rapid antidepressant response. In addition, this system may be a feasible target for developing treatments that have rapid and robust efficacy in individuals who have treatment-resistant depression and suicidal thoughts. We found that the glutamatergic modulator ketamine resulted in rapid, robust and relatively sustained antidepressant, antisuicidal, and anti-anhedonic effects. Response with ketamine occurred within 2 hours and lasted approximately 1 week. Comparable response rates with existing treatments occur at 6-8 weeks instead of hours. Study: (Biomarkers of rapid response in major depressive disorder). OBJECTIVE: To determine the neural correlates of rapid antidepressant response to the NMDA antagonist ketamine in subjects with major depressive disorder. We found robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist (ketamine); onset occurred within 2 hours post-infusion and continued to remain significant for 1 week. Aims are 1) to examine the antisuicidal effects of ketamine, and 2) to examine correlates of antidepressant response to ketamine in both major depressive disorder and bipolar disorder and include these data/outcome measures: clinical (e.g., family history), imaging (positron emission tomography PET, magnetic resonance imaging/spectroscopy), electrophysiological (magnetoencephalography MEG, electroencephalography EEG), neuropsychological, and biochemical (e.g., genetics, microRNA, BDNF, metabolomics). Results in the past year: NMDA-independent antidepressant actions of ketamine metabolite (2R,6R)-hydroxynorketamine. In this paper published in Nature 2016, we uncover the mechanism of how ketamine produces its rapid and sustained antidepressant effect. More importantly, we find that this effect takes place through one of its metabolites, (2R,6R)-hydroxynorketamine. This metabolite does not produce the dissociative and psychomimetic side effects or risk of abuse potential that ketamine has. This discovery has resulted in a series of drugs that could be developed for treatment-resistant depression that have rapid antidepressant effects and are well tolerated. 1. The role of adipokines in the rapid antidepressant effects of ketamine. In this project, we find that adipokines, which are cell signaling proteins secreted by the adipose tissue mediate the rapid antidepressant effects of ketamine. Adipokines have a key role in metabolism (including body mass index) and directly regulate inflammation and neuroplasticity pathways and also influence insulin sensitivity, bone metabolism and sympathetic outflow; all of these have been implicated in mood disorders 2. Pre-treatment differences in BOLD response to emotional faces correlate with antidepressant response to scopolamine. Intravenous administration of scopolamine (used for sea-sickness) produces rapid antidepressant effects. Here we show that a BOLD response to emotional faces correlates with the antidepressant effects of scopolamine. This work has importance because it begins to tease how prior to treatment who might or might not respond to a particular treatment intervention before the treatment is administered. 3. Single-dose infusion ketamine and non-ketamine N-methyl-D-aspartate receptor antagonists for unipolar and bipolar depression. In this study, we conducted a meta-analysis of efficacy, safety and time trajectories of all studies of ketamine in treatment-resistant depression. We confirmed that ketamine in multiple centers did indeed produce rapid and relatively sustained antidepressant efficacy in patients with treatment-resistant depression. This meta-analysis supports our work and findings to date with ketamine in depression. 4. Ketamine has rapid anti-fatigue effects in patients with depression. In a reanalysis of data from our ongoing studies, we demonstrate that ketamine produces rapid and relatively sustained anti-fatigue effects in patients with depression. This finding is important as it could give us clues to drugs that might produce rapid anti-fatigue effects for a variety of medical disorders and other conditions. 5. Assessing measures of suicidal ideation in clinical trials with a rapid-acting antidepressant. In this project, we assessed measures of suicidal thinking in subjects who participated in our ketamine studies. We demonstrate that some measures are reliable in measuring suicidal thinking and response to treatment.